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Table of Contents
LETTER TO THE EDITOR
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 800-802

Concurrent PIK3CA mutation: A cause for primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors or an acquired phenomenon?


1 Department of Molecular Oncology and Cancer Genetics, Dr. AV Institute of Personalized Cancer Therapy and Research, Gurgaon, Haryana; Department of Molecular Oncology and Cancer Genetics, Max Hospital, Saket, New Delhi, India
2 Department of Medical Oncology, Acibadem Health Group, Acibadem Adana Hospital, Adana, Turkey
3 Research & Development, MolQ Laboratory, Molecular Quest Healthcare Pvt Ltd., Gurgaon, Haryana, India

Date of Submission02-Nov-2021
Date of Decision22-Nov-2021
Date of Acceptance24-Nov-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Amit Verma
Dr. AV Institute of Personalized Cancer Therapy and Research, Gurgaon, Haryana; Max Hospital, Saket, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_256_21

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How to cite this article:
Verma A, Disel U, Kaur J. Concurrent PIK3CA mutation: A cause for primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors or an acquired phenomenon?. Cancer Res Stat Treat 2021;4:800-2

How to cite this URL:
Verma A, Disel U, Kaur J. Concurrent PIK3CA mutation: A cause for primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors or an acquired phenomenon?. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Jan 20];4:800-2. Available from: https://www.crstonline.com/text.asp?2021/4/4/800/334201



Kapoor et al.'s article in the molecular tumor board (MTB) section titled, “Concurrent epidermal growth factor receptor (EGFR) and PIK3CA mutations in non-small-cell lung cancer (NSCLC),”[1] is the reflection of one of the various clinical scenarios and challenges a treating physician encounters while practicing the art of “precision oncology.” Debating on each aspect of the genomic findings and their clinical relevance, curating the published evidence, juggling between the expert opinions, and reaching a consensus for an acceptable treatment option(s) have become an integral part of MTB discussions.

This interesting case study of concurrent EGFR and PIK3CA mutations in NSCLC brings out various clinically relevant points, which need to be highlighted.[1] In routine clinical practice, the use of a single sequential approach for biomarker testing would not have picked up the PIK3CA alteration (Exon 20, Met1043Ile) as observed in the study. However, a multigene next-generation sequencing (NGS) assay unraveled the mystery of the unexpected early failure with the first-generation tyrosine kinase inhibitor (TKI). Therefore, whether we should use NGS upfront in all cases becomes a point of debate. Further, the failure to identify the driver EGFR mutations (Exon 19, Leu747_Thr751 deletion) in cell-free DNA-based testing attempted once at the time of progression suggests either a true loss of the EGFR-mutant clone or the erratic and unpredictable shedding of the tumor DNA. Thus, repeated attempts at cell-free DNA-based testing are required to delineate a true from a false negative.

EGFR-activating mutations predict a favorable treatment response with EGFR-directed TKIs, but acquired resistance develops eventually such as the EGFR T790M mutation (which was not observed in this case study).[2] The PI3K/AKT pathway is important in oncogenesis and is downstream of the EGFR signaling pathway and has been reported to have a correlation with poor survival of patients with NSCLC. In about 5% of the patients with acquired resistance to EGFR TKIs, PIK3CA mutations have been reported to play a role.[3] In NSCLC, the commonly identified PIK3CA mutations include c. 1624G > A (p.E542K), c. 1633G > A (p.E545K), c. 3140A > G (p.H1047R), and c. 3140A > T (p.H1047 L).[4] The PIK3CA M1043I mutation observed in this case study is a rare alteration, reported to be present in 0.13% of AACR GENIE cases, with breast invasive ductal and lobular carcinomas, colon adenocarcinoma, and endometrial endometrioid adenocarcinoma having the greatest prevalence.[5] Whether this rare PIK3CA M1043I mutation was the cause for primary resistance to TKIs or was acquired during the course of treatment cannot be commented on as NGS was performed on the relapsed repeat liver biopsy block and not on the treatment-naïve tissue block. However, a close evaluation of the variant allele frequency (VAF) suggests that the TP53 mutation could likely be an early truncal event (VAF 53.2%), followed by EGFR (VAF 36.8%) as a late truncal event, followed by PIK3CA as a branched event (VAF 24.4%; almost half of TP53 VAF). This difference in the VAF depicts clonal evolution and suggests tumor heterogeneity or somatic mosaicism. Paired treatment-naïve and posttreatment tissue block NGS analysis may provide more insights into the phylogeny.

A few previous studies cited by the authors to suggest the role of PIK3CA mutations in primary EGFR TKI resistance do not appear to be convincing and robust.[6],[7] Engelman et al. showed in a preclinical model that introduction of an activating PIK3CA c. 1633G > A (p.E545K) mutation in the EGFR mutation-positive cell line, HCC827, conferred resistance to gefitinib.[6] However, as we understand, in vitro cell line experiments involve monoclonal homogenous population of cells treated in a controlled environment, and hence, their results may not be representative of those for the real-world polyclonal heterogenous population encountered in clinical practice. In addition, Ludovini et al. described a shorter time to progression (median 2.3 vs. 6.0 months; P = 0.01) and overall survival (median 9.9 vs. 30.2 months; P < 0.001) in 6 patients harboring a PIK3CA mutation treated with first-generation EGFR TKIs.[7] However, the patient cohort was too small to reach a definitive conclusion. Contrarily, Wu et al. in 2016 reported no significant difference in treatment response and progression-free survival for EGFR TKI between PIK3CA mutation-positive and negative patients (n = 344). Further, the PIK3CA mutation rate in patients with acquired resistance to EGFR TKIs was not higher than that in EGFR TKI-naïve patients.[8]

Similar to EGFR mutations, the PIK3CA mutations are oncogenic drivers. Tumors usually harbor a single oncogenic driver, and the presence of another oncogene is often not expected. This is the so-called mutual exclusivity rule of driver alterations in cancer.[9] Other mutations, if present, are mostly either passenger mutations or are responsible for resistance and evolution of the tumor, such as truncal and branch mutations that diverge from the truncal tree.

Further, in the current case study, although the MTB's recommendation to use the PIK3CA inhibitor, alpelisib, was appropriate, other treatment options such as EGFR TKI with chemotherapy or with PIK3CA/mTOR/AKT inhibitor could also be considered. In view of the relatively low VAF of the PIK3CA mutation in this case depicting heterogeneity, monotherapy with alpelisib may not produce a durable response.

Given the contradictory published data, it is difficult to ascertain if the PIK3CA mutation in this case study was the sole reason for primary resistance to the EGFR TKI or was an acquired event that occurred during the disease course under the treatment selection pressure. Therefore, to obtain deeper insights, even in a cost-constrained and resource-limited country like India, wherever feasible, multigene NGS should be preferred upfront. The MTB's decision arrived at with the highest ethical standards should be perceived as “acceptable or appropriate” rather than dichotomizing it as “right or wrong.” In India, there is an unmet need for institutional MTBs, and we strongly advocate expanding the access of these institutional MTBs to physicians outside the institution to participate in the existing MTBs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kapoor A, Noronha V, Shetty OA, Kashyap L, Kumar A, Chandrani P, et al. Concurrent EGFR and PIK3CA mutations in non-small-cell lung cancer. Cancer Res Stat Treat 2021;4:541-6.  Back to cited text no. 1
  [Full text]  
2.
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53.  Back to cited text no. 2
  [Full text]  
3.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26.  Back to cited text no. 3
    
4.
Chaft JE, Arcila ME, Paik PK, Lau C, Riely GJ, Pietanza MC, et al. Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther 2012;11:485-91.  Back to cited text no. 4
    
5.
AACR Project GENIE Consortium. AACR project GENIE: Powering precision medicine through an international consortium. Cancer Discov 2017;7:818-31.  Back to cited text no. 5
    
6.
Engelman JA, Mukohara T, Zejnullahu K, Lifshits E, Borrás AM, Gale CM, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest 2006;116:2695-706.  Back to cited text no. 6
    
7.
Ludovini V, Bianconi F, Pistola L, Chiari R, Minotti V, Colella R, et al. Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J Thorac Oncol 2011;6:707-15.  Back to cited text no. 7
    
8.
Wu SG, Chang YL, Yu CJ, Yang PC, Shih JY. The role of PIK3CA mutations among lung adenocarcinoma patients with primary and acquired resistance to EGFR tyrosine kinase inhibition. Sci Rep 2016;6:35249.  Back to cited text no. 8
    
9.
Kim YA, Madan S, Przytycka TM. WeSME: Uncovering mutual exclusivity of cancer drivers and beyond. Bioinformatics 2017;33:814-21.  Back to cited text no. 9
    



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[Pubmed] | [DOI]



 

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